The capacity of B lymphocytes to self-present peptides from their antibody variable (V) regions in the context of class II MHC is at the root of an important regulatory paradox:how is antigen specific T cell help delivered to B cells in the face of potential unregulated help delivered via "receptor presentation"? During the past funding period, we have obtained evidence that T cell help directed to somatically-mutated Ig V region peptides leads to spontaneous recruitment of autoreactive B lymphocytes in systemic lupus erythematosus (SLE). Accordingly, this application will address the issue of how somatically-generated antibody diversity is perceived and handled by an immune system that must otherwise provide antigen-specific and MHC-restricted help to B cells during the course of physiological immunity. We will test the hypothesis that tolerance is specifically attained to somatic mutational diversity, either in the T cell repertoire or in the B cell repertoire. In situ studies will be performed to reveal potential cognate interactions between B and T lymphocytes that might be responsible for tolerance. The possibility that immunoregulation is achieved by a segregation mechanism rather; than through tolerance will be considered. And we will develop a model to explore potential tolerance to preimmune but somatically-derived complex CDR3 diversity. The results acquired from this work will significantly advance our comprehension of important regulatory events that determine immunity in the face of impending autoimmune potential. And they will provide a roadmap to the design of therapeutic monoclonal antibodies that are both functional and nonimmunogenic.